Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect


The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL-1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC50<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC50>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.


Vyšlo v časopise: Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect. PLoS Pathog 6(9): e32767. doi:10.1371/journal.ppat.1001091
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001091

Souhrn

The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL-1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC50<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC50>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.


Zdroje

1. PerryBD

RandolphTF

1999 Improving the assessment of the economic impact of parasitic diseases and of their control in production animals. Vet Parasitol 84 145 168

2. DrudgeJH

LelandSEJr

WyantZN

1957 Strain variation in the response of sheep nematodes to the action of phenothiazine. II. Studies on pure infections of Haemonchus contortus. Am J Vet Res 18 317 325

3. AtanasioA

BoomkerJ

SitoeC

2002 A survey on the occurrence of resistance to anthelmintics of gastrointestinal nematodes of goats in Mozambique. Onderstepoort J Vet Res 69 215 220

4. ColesGC

RhodesAC

WolstenholmeAJ

2005 Rapid selection for ivermectin resistance in Haemonchus contortus. Vet Parasitol 129 345 347

5. JacksonF

CoopRL

2000 The development of anthelmintic resistance in sheep nematodes. Parasitology 120 Suppl S95 107

6. TraversaD

PaolettiB

OtrantoD

MillerJ

2007 First report of multiple drug resistance in trichostrongyles affecting sheep under field conditions in Italy. Parasitol Res 101 1713 1716

7. WaghornTS

LeathwickDM

RhodesAP

LawrenceKE

JacksonR

2006 Prevalence of anthelmintic resistance on sheep farms in New Zealand. N Z Vet J 54 271 277

8. KaminskyR

DucrayP

JungM

CloverR

RufenerL

2008 A new class of anthelmintics effective against drug-resistant nematodes. Nature 452 176 180

9. KaminskyR

GauvryN

Schorderet WeberS

SkripskyT

BouvierJ

2008 Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate. Parasitol Res 103 931 939

10. RufenerL

MaserP

RoditiI

KaminskyR

2009 Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel. PLoS Pathog 5 e1000380

11. MillarNS

GottiC

2009 Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 56 237 246

12. KohlerP

2001 The biochemical basis of anthelmintic action and resistance. Int J Parasitol 31 336 345

13. RobertsonAP

ClarkCL

BurnsTA

ThompsonDP

GearyTG

2002 Paraherquamide and 2-deoxy-paraherquamide distinguish cholinergic receptor subtypes in Ascaris muscle. J Pharmacol Exp Ther 302 853 860

14. Holden-DyeL

WalkerRJ

2006 Actions of glutamate and ivermectin on the pharyngeal muscle of Ascaridia galli: a comparative study with Caenorhabditis elegans. Int J Parasitol 36 395 402

15. ArenaJP

LiuKK

ParessPS

SchaefferJM

CullyDF

1992 Expression of a glutamate-activated chloride current in Xenopus oocytes injected with Caenorhabditis elegans RNA: evidence for modulation by avermectin. Brain Res Mol Brain Res 15 339 348

16. CulettoE

BaylisHA

RichmondJE

JonesAK

FlemingJT

2004 The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem 279 42476 42483

17. FlemingJT

SquireMD

BarnesTM

TornoeC

MatsudaK

1997 Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits. J Neurosci 17 5843 5857

18. BrownLA

JonesAK

BuckinghamSD

MeeCJ

SattelleDB

2006 Contributions from Caenorhabditis elegans functional genetics to antiparasitic drug target identification and validation: nicotinic acetylcholine receptors, a case study. Int J Parasitol 36 617 624

19. WilliamsonSM

WalshTK

WolstenholmeAJ

2007 The cys-loop ligand-gated ion channel gene family of Brugia malayi and Trichinella spiralis: a comparison with Caenorhabditis elegans. Invert Neurosci 7 219 226

20. ChenN

HarrisTW

AntoshechkinI

BastianiC

BieriT

2005 WormBase: a comprehensive data resource for Caenorhabditis biology and genomics. Nucleic Acids Res 33 D383 389

21. The UniProt Consortium 2009 The Universal Protein Resource (UniProt). Nucleic Acids Res 37 D169 174

22. AltschulSF

GishW

MillerW

MyersEW

LipmanDJ

1990 Basic local alignment search tool. J Mol Biol 215 403 410

23. BirneyE

ClampM

DurbinR

2004 GeneWise and Genomewise. Genome Res 14 988 995

24. FinnRD

TateJ

MistryJ

CoggillPC

SammutSJ

2008 The Pfam protein families database. Nucleic Acids Res 36 D281 288

25. LarkinMA

BlackshieldsG

BrownNP

ChennaR

McGettiganPA

2007 Clustal W and Clustal X version 2.0. Bioinformatics 23 2947 2948

26. RiceP

LongdenI

BleasbyA

2000 EMBOSS: the European Molecular Biology Open Software Suite. Trends Genet 16 276 277

27. HusonDH

RichterDC

RauschC

DezulianT

FranzM

2007 Dendroscope: An interactive viewer for large phylogenetic trees. BMC Bioinformatics 8 460

28. BinghamJ

SudarsanamS

2000 Visualizing large hierarchical clusters in hyperbolic space. Bioinformatics 16 660 661

29. BlaxterML

De LeyP

GareyJR

LiuLX

ScheldemanP

1998 A molecular evolutionary framework for the phylum Nematoda. Nature 392 71 75

30. TasneemA

IyerLM

JakobssonE

AravindL

2005 Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome Biol 6 R4

31. ChiuJ

DeSalleR

LamHM

MeiselL

CoruzziG

1999 Molecular evolution of glutamate receptors: a primitive signaling mechanism that existed before plants and animals diverged. Mol Biol Evol 16 826 838

32. PhilippeG

AngenotL

TitsM

FrederichM

2004 About the toxicity of some Strychnos species and their alkaloids. Toxicon 44 405 416

33. KallL

KroghA

SonnhammerEL

2004 A combined transmembrane topology and signal peptide prediction method. J Mol Biol 338 1027 1036

34. KallL

KroghA

SonnhammerEL

2007 Advantages of combined transmembrane topology and signal peptide prediction–the Phobius web server. Nucleic Acids Res 35 W429 432

35. JonesAK

SattelleDB

2004 Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays 26 39 49

36. WilliamsonSM

RobertsonAP

BrownL

WilliamsT

WoodsDJ

2009 The nicotinic acetylcholine receptors of the parasitic nematode Ascaris suum: formation of two distinct drug targets by varying the relative expression levels of two subunits. PLoS Pathog 5 e1000517

37. RufenerL

BaurR

KaminskyR

MaserP

SigelE

2010 Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus. Molecular Pharmacology In Press

38. SagerH

HoskingB

BapstB

SteinP

VanhoffK

2009 Efficacy of the amino-acetonitrile derivative, monepantel, against experimental and natural adult stage gastro-intestinal nematode infections in sheep. Vet Parasitol 159 49 54

39. GhedinE

WangS

SpiroD

CalerE

ZhaoQ

2007 Draft genome of the filarial nematode parasite Brugia malayi. Science 317 1756 1760

40. OppermanCH

BirdDM

WilliamsonVM

RokhsarDS

BurkeM

2008 Sequence and genetic map of Meloidogyne hapla: A compact nematode genome for plant parasitism. Proc Natl Acad Sci U S A 105 14802 14807

41. AbadP

GouzyJ

AuryJM

Castagnone-SerenoP

DanchinEG

2008 Genome sequence of the metazoan plant-parasitic nematode Meloidogyne incognita. Nat Biotechnol 26 909 915

42. SteinLD

BaoZ

BlasiarD

BlumenthalT

BrentMR

2003 The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol 1 E45

43. C. elegans Seq Consortium 1998 Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282 2012 2018

44. DieterichC

CliftonSW

SchusterLN

ChinwallaA

DelehauntyK

2008 The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism. Nat Genet 40 1193 1198

45. BerrimanM

HaasBJ

LoVerdePT

WilsonRA

DillonGP

2009 The genome of the blood fluke Schistosoma mansoni. Nature 460 352 358

46. AparicioS

ChapmanJ

StupkaE

PutnamN

ChiaJM

2002 Whole-genome shotgun assembly and analysis of the genome of Fugu rubripes. Science 297 1301 1310

47. Int. Chicken Genome Seq. Consortium 2004 Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432 695 716

48. SheX

JiangZ

ClarkRA

LiuG

ChengZ

2004 Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431 927 930

49. ElsikCG

TellamRL

WorleyKC

GibbsRA

MuznyDM

2009 The genome sequence of taurine cattle: a window to ruminant biology and evolution. Science 324 522 528

50. Lindblad-TohK

WadeCM

MikkelsenTS

KarlssonEK

JaffeDB

2005 Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438 803 819

51. AdamsMD

CelnikerSE

HoltRA

EvansCA

GocayneJD

2000 The genome sequence of Drosophila melanogaster. Science 287 2185 2195

52. NeneV

WortmanJR

LawsonD

HaasB

KodiraC

2007 Genome sequence of Aedes aegypti, a major arbovirus vector. Science 316 1718 1723

53. HoltRA

SubramanianGM

HalpernA

SuttonGG

CharlabR

2002 The genome sequence of the malaria mosquito Anopheles gambiae. Science 298 129 149

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa